Variant: NM_000218.3(KCNQ1):c.1927G>A (p.Gly643Ser)

CA006598

36437 (ClinVar)

Gene: KCNQ1

Condition: long QT syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 716e9ead-e527-4006-a249-fe069b6d78ab

Approved on: 2025-07-01

Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.1927G>A
NM_000218.3(KCNQ1):c.1927G>A (p.Gly643Ser)
NC_000011.10:g.2847899G>A
CM000673.2:g.2847899G>A
NC_000011.9:g.2869129G>A
CM000673.1:g.2869129G>A
NC_000011.8:g.2825705G>A
NG_008935.1:g.407909G>A
ENST00000496887.7:c.1570G>A
ENST00000155840.12:c.1927G>A
ENST00000335475.6:c.1546G>A
ENST00000526095.2:c.331G>A
ENST00000155840.9:c.1927G>A
ENST00000335475.5:c.1546G>A
ENST00000526095.1:n.434G>A
NM_000218.2:c.1927G>A
NM_181798.1:c.1546G>A
NR_130721.1:n.778-7457C>T

Benign

• Met criteria codes: BA1

• Not Met criteria codes: BS3 BS4 BS1 BS2 BP7 BP3 BP4 BP1 BP2 PS1 PS3 PS2 PS4 PP3 PP2 PP4 PP1 PVS1 PM6 PM2 PM5 PM1 PM4 PM3

Expert Panel

Potassium Channel Arrhythmia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Potassium Channel Arrhythmia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KCNQ1 Version 1.0.0

Evidence submitted by expert panel

Potassium Channel Arrhythmia VCEP

NM_000218.3(KCNQ1):c.1927G>A is a missense variant predicted to cause substitution of glycine by serine at amino acid 643 (p.Gly643Ser). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.04778, with 2,047 alleles / 42,844 total alleles and 53 homozygotes in the East Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.004 (BA1). This variant has been identified in individuals with LQTc interval including 3 who had QTc interval over 480ms, as well as an individual with sudden unexplained death, however their phenotypes do not meet criteria for being highly specific to LQTS (PMID 15028050; PMID: 26385840). The variant is seen frequently in control individuals vs cases (PMID: 26159999; PMID: 18426444). From in-vitro studies, this variant is thought to have a weak dominant-negative effect without much alteration to its kinetic properties (PMID: 11761407; PMID: 22378279). This variant is thought to be a risk factor/predisposition to arrhythmias or acquired LQTS, but is not thought to be a risk factor for congenital LQTS. The computational predictor REVEL gives a score of 0.566, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.2 and does not strongly predict a damaging effect on KCNQ1 splicing. In summary, this variant meets the criteria to be classified as benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmias VCEP: BA1. (VCEP specifications version 1.0.0; date of approval 03/04/2025).

Met criteria codes

• BA1: The highest population minor allele frequency in gnomAD v4.0 is 0.04778 (2047/42844 alleles) in East Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP threshold (>0.001 (0.1%)) for BA1, and therefore meets this criterion (BA1).

Not Met criteria codes

• BS3: Coexpression of WT-KCNQ1 and G643S-KCNQ1 with KCNE1 resulted in 30% reduction in the slow delayed rectier K1 current IKs without much alteration in the kinetic properties except its deactivation process, suggesting that the 643S substitution had a weaker dominant-negative effect on the heteromultimeric channel complexes. (PMID: 11761407; PMID: 22378279)
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: Not applicable due to incomplete penetrance. Observed in 73 homozygotes in gromAd v4.0
• BP7: Missense variant
• BP3: Missense variant
• BP4: Computational evidence suggest inconclusive impact on expression (Revel score is 0.566 which is between 0.25-0.75). Splice site prediction tools suggest that this variant does not impact splicing (spliceAI: 0.0)
• BP1: Not applicable, as pathogenic KCNQ1 variants are not limited to truncating variants, but can be missense as well.
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Benign (PMID: 26159999; PMID: 18426444)
• PP3: Computational evidence suggest inconclusive impact on expression (Revel score is 0.566 which is between 0.25-0.75). Splice site prediction tools suggest that this variant does not impact splicing (spliceAI: 0.0)
• PP2: Not applicable due to presence of benign variation throughout the KCNQ1 gene
• PP4: 5 patients, 3 with QTc over 480. No additional data to be "highly specific" (PMID 15028050; PMID: 26385840)
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: Missense variant
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: Missense variant
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline